SUMMARY The innate immune system is the front line of host defense against microbial infections, but its rapid and uncontrolled activation elicits microbicidal mechanisms that have deleterious effects. Increasing evidence indicates that the metazoan nervous system, which responds to stimuli originating from both the internal and the external environment, functions as a modulatory apparatus that controls not only microbial killing pathways but also cellular homeostatic mechanisms. However, given the complexity of the nervous and immune systems of mammals, the precise mechanisms by which the two systems influence one another remain understudied. This proposal describes experiments designed to elucidate the mechanism by which the nervous system may sense pathogens and/or probiotic microbe-associated molecular patterns (MAMPs) and control innate immunity. Using the nematode Caenorhabditis elegans, we have recently demonstrated that G-protein coupled receptor (GPCR) signaling in at least 9 different neurons controls immune responses, indicating that cell non- autonomous signals from different neurons may act on non-neural tissues to regulate innate immune responses at the organismal level. GPCR signaling in the aforementioned neurons controls microbial killing pathways and a conserved unfolded protein response pathway that may be necessary to alleviate the increased demand on protein folding during immune activation. In this proposal, we will use a variety of molecular and genetic techniques to explore the general hypothesis that the nervous system regulates immune homeostasis during the host response to pathogen infections at the whole animal level.